Persistent viruses, such as human immunodeficiency virus (HIV), cause major health problems worldwide and are extraordinarily difficult to clear following the establishment of persistence. Given the challenges associated with clearing persistent infections, it is important to develop and mechanistically understand therapeutic strategies that successfully achieve viral eradication without inducing permanent damage to the host. We model states of persistent infection in our laboratory using lymphocytic choriomeningitis virus (LCMV), a mouse as well as human pathogen. Persistent LCMV infections can be established by infecting mice in utero or by infecting adult mice intravenously with specific strains of the virus. When mice are persistently infected at birth or in utero with LCMV, the virus establishes systemic persistence, infecting both peripheral tissues as well as the central nervous system (CNS). Adult LCMV carrier mice are centrally tolerant to the virus at the T cell level and thus unable to eradicate the pathogen. We model persistent infection in adult mice by infecting with more aggressive strains of LCMV such as clone 13. Infection with clone 13 initiates a state of persistence that shares some important features with HIV-1 infection in humans, including infection / impairment of dendritic cells, exhaustion / deletion of the virus-specific T cells, and rapid establishment of viral persistence in the CNS as well as peripheral tissues. Both models LCMV persistence allow us to study how the immune system can be manipulated or supplemented to control a persistent viral infection in the periphery and CNS. One area of active research in the laboratory is the study of immune factors that control viral infections in the periphery and prevent their entry into the CNS. We recently studied a type I interferon (IFN-I)-inducible antiviral protein referred to as tetherin or BST-2. This host defense protein plays an important role in inhibiting the cellular release of many enveloped viruses, including HIV-1. To determine how this protein shapes the early antiviral defense to a persistent infection, we studied its role in the LCMV clone 13 model. Interestingly, we uncovered in vitro that BST-2 has only a modest affect on the release of LCMV virions from cultured cells. However, the antiviral effect of BST-2 is far more significant in vivo. In its absence, a persistence-prone strain of LCMV (clone 13) is no longer confined to the splenic marginal zone within the first few days of infection. Splenic marginal zone macrophages express BST-2 in response to IFN-I and likely use this protein to sequester viruses like LCMV that are captured from the blood. BST-2 deficiency allows LCMV clone 13 to quickly escape from the marginal zone, resulting in an altered distribution of LCMV-specific T cells and reduced T cell proliferation / function. This also delays viral control in the serum and promotes long-term viral persistence in the brain. These data demonstrate that BST-2 has an important role in shaping the anatomical distribution and adaptive immune response against a persistent viral infection in vivo. Within the CNS, we also focus on the immunotherapeutic clearance of persistently infected parenchymal cell populations like microglia and neurons. Microglia have become a centerpiece in our laboratory over the past few years given their plastic nature, interesting dynamic properties, and ability to orchestrate both sterile and antiviral immune responses. Following administration of adoptive immunotherapy into mice persistently infected from birth with LCMV, we observed that antiviral T cells recruited into the CNS promote the conversion of nearly all microglia into CD11c+ antigen presenting cells (APCs). CD11c is a marker commonly used to identify dendritic cells (DCs), and we have previously shown that interactions with host DCs are required for successful viral clearance following adoptive immunotherapy. Interestingly, microglia can also acquire DC-like properties following adoptive immunotherapy. They upregulate antigen-presenting machinery and release chemoattractants that recruit antiviral T cells. In fact, we showed using TPM that therapeutic antiviral CD8+ and CD4+ T cells directly engage CD11c+ microglia during adoptive immunotherapy. Even more impressive is the fact that these interactions result in viral clearance from microglia without evidence of cytopathology. We obtained data showing that microglia are resistant to apoptosis and are purged of virus in a noncytopathic manner. We postulate that microglia have acquired a mechanism to dampen the cytopathic effector mechanisms of T cells in order to help preserve brain tissue during viral clearance. Another aspect of our infectious disease research is to understand how tissues like the CNS return to homeostasis after a pathogen is cleared. We recently discovered that resolution of viral infection in the meninges is associated with peripheral immune cell engraftment. Under steady state, the meninges are inhabited by long-lived tissue resident macrophages. Upon viral infection, we observed that the meninges become heavily infiltrated by peripheral monocytes that engraft the meningeal niche and remain in situ for months after viral clearance. These cells possessed functional properties that were different than those of resident meningeal macrophages, including a loss of bacterial and immunoregulatory sensors. These data demonstrate that even clearance of a infection can imprint a tissue with new functional properties and alter its ability to respond to future challenges. Conceptually, this finding adds a new level of complexity to our understanding of how diseases could develop after a pathogen is cleared.